ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.680T>G (p.Ile227Ser) (rs121917937)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Bioinformatics, Peking University RCV000059455 SCV000221837 pathogenic Severe myoclonic epilepsy in infancy 2014-12-20 criteria provided, single submitter research
GeneDx RCV000188842 SCV000242472 pathogenic not provided 2015-12-24 criteria provided, single submitter clinical testing The I227S missense variant in the SCN1A gene has been reported previously as a de novo pathogenic variant in association with Dravet syndrome and other SCN1A-related disorders (Nabbout et al., 2003; Mancardi, et al., 2006; SCN1A Variant Database). This variant is a non-conservative amino acid substitution that alters a highly conserved position in the transmembrane segment S4 (voltage sensor) of the first homologous domain, and functional studies indicate that it significantly impairs channel function (Ohmori et al., 2006). Therefore, the presence of Ile227Ser is consistent with a diagnosis of an SCN1A related disorder
Athena Diagnostics Inc RCV000188842 SCV000615047 pathogenic not provided 2016-04-04 criteria provided, single submitter clinical testing
Invitae RCV000636408 SCV000757847 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2019-07-28 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with serine at codon 227 of the SCN1A protein (p.Ile227Ser). The isoleucine residue is highly conserved and there is a large physicochemical difference between isoleucine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with severe myoclonic epilepsy of infancy, and at least four of them have been confirmed to be de novo (PMID: 12821740, 17054684). This variant has also been reported in multiple individuals affected with Dravet syndrome or unspecified epilepsy (PMID: 19589774, 22050978, 22147323, 23195492). ClinVar contains an entry for this variant (Variation ID: 68579). This variant identified in the SCN1A gene is located in the transmembrane D1-S4 region of the resulting protein (PMID: 25348405, 18804930), Experimental studies have shown that this missense change was nonfunctional, and failed to generate measurable sodium channel activity in a cellular biophysical analysis (PMID: 17054685). For these reasons, this variant has been classified as Pathogenic.
LifeCell International Pvt. Ltd RCV000059455 SCV001739362 pathogenic Severe myoclonic epilepsy in infancy criteria provided, single submitter clinical testing A heterozygous missense variant (c.680T>G) in exon 8 of the SCN1A gene that results in the amino acid substitution from Isoleucine to Serine at codon 227 (p.Ile227Ser) was identified. There is a large physicochemical difference between Isoleucine to Serine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The observed variant is not present in both the 1000 Genomes and gnomAD databases. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT are damaging. This variant has previously been reported for Dravet syndrome by Huang W et al., 2017. This variant is a non-conservative amino acid substitution that alters a highly conserved position in the transmembrane segment S4 (voltage sensor) of the first homologous domain, and functional studies indicate that it significantly impairs channel function (Ohmori et al., 2006). This variant has been previously classified as Pathogenic in ClinVar (Variation ID 68579 as of 2019-08-05) with respect to Dravet syndrome with a status of (2 stars) criteria provided, multiple submitters, no conflicts. The Missense Variants Z-Score for this variant is 5.61. Missense Variants Z-Score is produced by the Exome Aggregation Consortium (60,706 adult humans) by computing a signed Z score for the deviation of observed counts from the expected number. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer missense variants than expected. (DOI: 10.1038/nature19057). Based on the above evidence this variant has been classified as pathogenic according to the ACMG guidelines.
UniProtKB/Swiss-Prot RCV000059455 SCV000090980 not provided Severe myoclonic epilepsy in infancy no assertion provided not provided

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